N-substituted azabicyclononanes

ABSTRACT

N-SUBSTITUTED AZABICYCLO (3.2.2)NONANES IN THE FORM OF THE FREE BASE, ACID ADDITION SALTS OR QUATERNARY AMMONIUM SALTS ARE DISCLOSED WHERE THE N-SUBSTITUENT IS EITHER: (1) A 2-HYDROXYBENZYL ATTACHED THROUGH ITS METHYLENE PORTION AND ALSO CONTAINING ON THE BENZYL TWO OR THREE OTHER SUBSTITUENTS, NAMELY A CHLORO OR CYCLOPENTYL OR BENZYL IN THE 3-POSITION, A CHLORO OR FLUORO IN THE 5-POSITION, AND HYDROGEN OR CHLORO IN THE 6-POSITION, EXEMPLIFIED BY 3-(3CHLORO - 5 - FLUORO - 2-HYDROXYBENZYL)-3-AZABICYLCLO (3.2.2) NONANE, 3 - (3-BENZYL-5-CHLORO-2-HYDROXYBENZYL)-3-AZABICYCLO(3.2.2)NONANE, 3 - (5 - CHLORO-3-CYCLOPENTYL-2-HYDROXYBENZYL)- 3-AZABICYCLO(3.2.2)NONANE, 3-(2-HYDROXYL3,5,6-TRICHLOROBENZYL)-3-AZABICYCLO(3.2.2)NONANE, 3-(3,5DICHLORO-2-HYDROXYBENZYL)-3-AZABICYCLO(3.2.2)NONANE; OR (2) A STRAIGHT CHAIN C8-C14 ALKYL GROUP, EXEMPLIFIED BY 3(OCTYL OR DECYL OR DODECYL OR TETRADECYL)-3-AZABICYCLO(3. 2.2)NONANE. THE ACID ADDITION AND QUATERNARY AMMONIUM SALTS HAVE ANTIMICROBIAL ACTIVITY WHEN USED IN A CARRIER SUCH AS AQUEOUS-ORGANIC SOLVENT SOLUTION, SOAPS, OINTMENTS, PLASTICS, ADHESIVES, SUTURES, AND PAINTS.

United "States Patent 9 3,816,407 N-SUBSTITUTED AZABICYCLONONANES Howard C. Zell, Philadelphia, Pa., and Paul M. Borick, granford, N.J., assignors'to Arbrook, Inc., Arlington,

ex. No Drawing. Filed Dec. 16, 1970, Ser. No. 98,940 Int. Cl. C07d 41/04 U.S. Cl. 260-239 BA 6 Claims ABSTRACT OF THE DISCLOSURE N-substituted azabicyclo[3.2.2]nonanes in the form of the free base, acid addition salts or quaternary ammonium salts are disclosed where the N-substituent is either: (1) a 2-hydroxybenzyl attached through its methylene portion and also containing on the benzyl two or three other substituents, namely, a chloro or cyclopentyl or benzyl in the 3-position, a chloro or fluoro in the 5-position, and hydrogen or chloro in the 6-position, exemplified by 3-(3- chloro 5 fluoro Z-hydroxybenzyl)-3-azabicyclo[3.2.2] nonane, 3 (3-benzyl-5-chloro-2-hydroxybenzyl)-3-azabicyclo[3.2.2]nonane, 3 (5 chloro-3-cyclopentyl-2-hydroxybenzyl) 3-azabicyclo[3.2.2] nonane, 3-(2-hydroxyl- 3,5,6-trichlorobenzyl)-3-azabicyclo[3.2.2]nonane, 3-(3,5- dichloro-2-hydroxybenzyl)-3-azabicyclo[3.2.2]nonane; or (2) a straight chain C alkyl group, exemplified by 3- [octyl or decyl or dodecyl or tetradecyl]-3-azabicyclo[3. 2.2]nonane. The acid addition and quaternary ammonium salts have antimicrobial activity when used in a carrier such as aqueous-organic solvent solution, soaps, ointments, plastics, adhesives, sutures, and paints.

SUMMARY OF THE INVENTION This invention relates to a novel group of N-substituted azabicyclononanes, in the form of the free base, acid addition salts or quaternary ammonium salts, and to the use of the salts as antimicrobial agents.

The N-substituted azabicyclononanes are of the [3.2.2] type. The N-substituent is of two main types: (A) a 2- hydroxybenzyl attached through its methylene portion, in which the benzyl in addition to having a hydroxy in the 2-position always has two or three other substituents; having in the 3-position a chloro or cyclopentyl or benzyl group, while having in the 5-position a chloro or fluoro group; and having when there is another substituent, a chloro in the 6-position; and (B) a straight chain alkyl group of medium length having from 8 to 14 carbons in the chain.

Thus the compounds of the present invention are either of Formula (A) C\ OH N-CHr- Z wherein X is chloro or fluoro; Y is hydrogen or chloro; and Z is chloro or cyclopentyl or benzyl or Formula (B) 3,816,407 Patented June 11, 1974 wherein n is an integer from 8 to 14 and also includes the acid addition salts and quaternary ammonium salts of (A) and (B).

The compounds of the present invention, in the form of their acid addition and quaternary ammonium salts, have a high degree of antimicrobial activity against Grampositive bacteria, Gram-negative bacteria, and fungi in a relatively short time. The acid addition salts (which are the preferred ones) and the quaternary ammonium salts are usually crystalline solids which are relatively insoluble in water. They are soluble in various water-containing solvents, e.g. 50 percent dimethylformamide, and are tested for antimicrobial activity in such solvents, the free bases, which are inactive as antimicrobials, are used as intermediates to make the acid addition and quaternary ammonium salts.

GENERAL DESCRIPTION (A) Nomenclature The compounds of the present invention all can be named as azabicyclononanes. However, the quaternary ammonium forms will here be named as azoniabicyclononanes, which is an alternative form of nomenclature better suited for such compounds.

(B) Methods of preparation The acid addition salts of the N-alkyl substituted compounds of the present invention are made by refluxing equimolar amounts of 3-azabicyclo[3.2.2]nonane and the halide of the radical which is to be substituted on the nitrogen of the azabicyclononane in the final product in an anhydrous solvent, and then adding hydrogen chloride (or whatever other acid may be desired for other acid addition salts) in ether solution, to give the hydrochloride, which is then purified by recrystallization from water or another suitable solvent.

The other acid addition salts, i.e. where the N-substituent is the substituted hydroxybenzyl, are made by mixing 3-azabicyclo [3.2.2]nonane with the phenol ocrresponding to the N-substituent radical (e.g. where the substituent radical is 3-chloro-S-fluoro-Z-hydroxybenzyl, the reactant is 2-chloro-4-fluorophenol), using a slight excess of the azabicyclononane over the equimolar amount stoichiometrically required, in a solvent such as methanol, and then adding dropwise a slight excess over the equimolar amount required of formaldehyde in aqueous solution. The mixture is then refluxed, allowed to stand at room temperature, and the solvent and water are distilled off leaving an oily residue which is reacted with acid to form the desired acid addition salt, which after recrystallization from solvents is obtained as a solid.

A wide variety of acid addition salts have been made using both inorganic and organic acids, such as hydrochloric acid, hydroiodic acid, hydrobromic acid, sulfuric acid, oxalic acid, maleic acid, and d-tartaric acid, and insofar as we are aware any of the many acids known which have been used to make acid addition salts could be used in the present invention also. Examples of some of the more common acids which are often used include: nitric acid, phosphoric acid, citric acid, and lactic acid, which would give the nitrate, phosphate or acid phosphate, citrate or acid citrate, and lactate salts respectively.

The free base compounds of the present invention are obtained from the corresponding acid addition salts by alkaline hydrolysis in conventional manner. Those free bases where the N-substituent is the alkyl radical are obtained in the form of oily liquids while the other free base compounds of the invention are obtained as solids.

The quaternary ammonium compounds of the present invention are obtained as solids from the corresponding free bases by the addition thereto of alkyl esters of inorganic acids or other compounds as are commonly used to make quaternary ammonium salts in conventional fashion.

Examples of some such typical materials often used to make quaternary ammonium salts include such compounds as methyl chloride, methyl bromide, methyl iodide, ethyl bromide, propyl bromide, benzyl chloride, benzyl bromide, methyl sulfate, methyl benzenesulfonate, and methyl p-toluenesulfonate, giving the methochloride, methobromide, methoiodide, ethobromide, propobrornide, benzochloride, benzobromide, methosulfate, methobenzenesulfonate, and metho-p-toluenesulfonate salts, respectively.

It is possible to go in known fashion from one acid addition salt to another by hydrolyzing to obtain the free base and then reacting it with a different acid to make a different acid addition salt. Thus the free base can be used to make the other forms.

(C) Utility and test procedures used The compounds of the present invention are best used as antimicrobial agents in the form of their acid addition and quaternary ammonium salts, which forms are soluble in water or aqueous organic solvents. Their antimicrobial effect in aqueous solutions indicates they can be used as disinfecting solution for instruments, aerosol disinfectants, floor and wall disinfectants, fogging solutions, laundry disinfectants, hand scrub disinfectants, de-germing lotions, and can be incorporated into paints, plastics, textiles, etc., to impart antimicrobial activity, e.g., gloves, trash bags, sheets, tarpaulins, etc., or incorporated into sutures and adhesives to make these devices antimicrobial in nature. Illustrative compositions are shown in the specification after the examples.

The quaternary ammonium compounds can also be used as anticoagulant complexing agents.

In determining the outstanding antimicrobial activities of the compounds of the present invention the following stringent standard test procedures were used:

Screening procedure One liter of a 1 percent solution (preferably aqueous) of the compound being examined is prepared. Other specific systems which are acceptable in addition to water are ethylene glycol, glycerine, aqueous 20 percent ethanol, 20 percent isopropanol, 20 percent acetone, 50 percent dimethylforrnamide, 50 percent dimethylsulfoxide, 20 percent M-Pyrol (N-methyl-2-pyrrolidone) and 20 percent 2-Pyrol (2-pyrrolidone). These solvents have no independent antimicrobial efiect.

Into each of ten test tubes is placed 100 ml. of the test solution at 20 C. One test tube is used for each microorganism and three time intervals are employed. Three polished stainless steel cylinders (penicillin cup, peni-cylinder) are impregnated by dipping into a culture of each organism. The cylinders are removed and dried at 37 C. in the case of vegetative organisms, and at room temperature if spores are being impregnated. These cylinders are placed in each tube of solution and removed after a given time interval and placed in tubes of culture media. Those tubes of culture media which show no growth after a given time of incubation indicate activity while those. which show growth indicate lack of activity in the compound under test.

The test procedure is adapted from published procedures, the references for which are given below:

Bactericidal activity Adaptation of the Use-Dilution Method or Primary Evaluations of Disinfectants, D. F. Ortenzio and L. S. Stuart, Journal of AOAC, 44, 416 (1961).

Time intervals: 1, 5, minutes.

Fungicidal activity Methods of analysis-AOAC, 9th edition, p. 69 (1960). Time intervals: 1, 5, 10 minutes.

The results of the tests are interpreted as marked activity, i.e. killing of bacteria and fungi in less than one minute or l-S minutes; good activity, i.e. killing of bacteria and fungi in 1-5 or 5-10 minutes; slight activity, i.e. killing of bacteria and fungi in less than ten minutes.

The spectrum of microorganisms used in the screening test is as follows:

Gram-positive bacteria:

Staphylococcus aureus Streptococcus pyogenes Diplococcus pneumoniae Gram-negative bacteria:

Escherichia coli Pseudomonas aeruginosa Salmonella choleraesuis Fungi:

Candida albicans Trichophyton interdigitale.

The actual results obtained for various representative corresponding compounds of the present invention are shown in the corresponding specific examples.

The following examples are illustrative of the best mode of carrying out the invention. They are for purposes of illustration and are not to be construed as limiting the invention to the specific details given.

Preparation A.3-azoniabicyclo[3.2.2]nonane chloride: To a solution of 62.5 g. (0.5 mole) of 3-azabicyclo [3.2.2]nonane in ml. of isopropyl alcohol was added with stirring and cooling 141 ml. of 7.4 N hydrogen chloride in absolute ethanol. A white solid separated. After the mixture was chilled for three hours, the solid was filtered under suction and dried at 60 C. Thus was obtained 53.5 g. of 3-azoniabicyclo[3.2.2]nonane chloride, M.P. 297-302 C. (d.).

An alternate name for this known compound is azabicyclo[3.2.2]nonane hydrochloride.

EXAMPLE I 3-octyl-3-azabicyclo[3.2.2]nonane hydrochloride A mixture consisting of 37.56 g. (0.3 mole) of 3-azabicyclo[3.2.2]nonane, 59.9 g. (0.3 mole) of l-bromooctane and 15.9 g. (0.15 mole) of anhydrous sodium carbonate in 450 ml. of absolute ethanol was stirred under reflux for 24 hours.

The cooled reaction mixture was filtered and the ethanol was distilled from the filtrate under reduced pressure. The distillation residue, a mixture of an orange solid and an oil, was stirred with 300 ml. of diethyl ether. A solid, which was insoluble in the ether, was removed by filtration. To the filtrate was added with stirring 300 ml. of absolute ether and 45 ml. of a 7.4 N solution of hydrogen chloride in absolute ethanol. The cloudy solution which resulted was chilled.

The solid which had formed in the acidified filtrate was filtered, washed with ether, and dried at 60 C. There was obtained 59.3 g. of solid, M.P. 253-256" C. (d.).

After three recrystallizations from water, a solid, 13.7 g., M.P. 253255 C. (d.), was obtained. A final recrystallization of 5 g. of this product from benzene-ethanol yielded 3.0 g. of the pure product, 3-octyl-3-azabicyclo [3.2.2]nonaue hydrochloride, M.P. 252254 C. (d.).

Analysis.Calcd for C H C1N: C, 70.16; H, 11.78; N, 5.12. Found: C, 69.67, 69.54; H, 11.6; N, 4.93.

EXAMPLE II 3-octyl-3-azabicyclo[3.2.2]nonane To a mixture of 74.1 g. (0.271 mole) of 3-octyl-3-azabicyclo[3.2.2]nonane hydrochloride in 400 ml. of water was added 30 ml. (0.3 mole) of 10 N sodium hydroxide solution with vigorous stirring. The alkaline mixture was extrac ed wi h three 200 mlportions of diethyl ether.

The combined ether extracts were washed with two 50 ml. portions of distilled water by shaking in a separatory funnel. The ether layer was filtered and the filtrate was dried by means of anhydrous sodium sulfate. The dry ether extracts were filtered to remove the sodium sulfate and the ether was distilled from the filtrate under reduced pressure.

The oily residue which resulted was distilled under reduced pressure to obtain 34.4 g. of a clear oil, B.P. at 0.4 mm. of mercury, 105-108 C.; N 1.4765, which was pure 3-octyl-3-azabicyclo[3.2.2]nonane.

Analysis.Calcd for C H N: C, 80.94; H, 13.16; N, 5.90. Found: C, 81.14; H, 13.16; N, 5.91.

EXAMPLE HI 3-methyl-3-octyl-3-azoniabicyclo[3.2.2]nonane iodide A mixture of 4 g. (0.0169 mole) of 3-octyl-3-azabicyclo[3.2.2]nonane, 9.6 g. (0.0676 mole) of methyl iodide and 150 ml. of methanol was heated to reflux. A clear solution resulted and the solution was cooled to room temperature and concentrated to a volume of 50 ml. The concentrate was refrigerated overnight. A small amount of solid which had formed was removed by filtration and discarded. The filtrate was concentrated to dryness and a white solid was obtained.

The while solid was recrystallized from acetone-ethyl acetate, ethanol-hexane, ethanol-ether, acetone-hexane and finally acetone-ethyl acetate to obtain 0.4 g. of analytically pure product, 3-methyl-3-octyl-3-azoniabicyclo [3.2.2]nonane iodide, M.P. 196 C. (d.).

Analysis.-Calcd for C H IN: C, 53.82; H, 9.03; N, 3.69; I, 33.45. Found: C, 53.69; H, 8.80; N, 3.50; I, 33.34.

EXAMPLE IV 3-decyl-3-azabicyclo [3.2.2]nonane hydrochloride A mixture consisting of 12.52 g. (0.1 mole) of 3-azabicyclo[3.2.2]nonane, 17.67 g. (0.1 mole) of l-chlorodecane and 5.3 g. (0.05 mole) of anhydrous sodium carbonate in 150 ml. of absolute ethanol was stirred under reflux for 24 hours.

The cooled reaction mixture was filtered. To the filtrate was added 41.7 ml. of 3 N hydrochloric acid and a white solid separated. After recrystallizations from water, a white solid, 12.87 g., M.P. 243-245 C. (d.), was obtained as the pure product, 3-decyl-3-azabicyclo[3.2.2] nonane hydrochloride.

Analysis.'Calcd for C H ClN: C, 71.60; H, 12.02; N, 4.64. Found: C, 71.67; H, 11.95; N, 4.74.

3-decyl-3-azabicyclo[3.2.2]nonane hydrochloride was tested against various microorganisms, and the results obtained were as follows:

Organism: Killing time in minutes S. aureus Str. pyogenes 1-5 D. pneumoniae 1-5 E. coli 1 Ps. aeruginosa 10 Sal. choleraesuis -5 1-5 C. albicans 1 T. interdigitale 1 EXAMPLE V 3-decyl-3-azabicyclo[3.2.2]nonane hydroiodide 6 Analysis.Ca1cd for C H IN: C, 54.95; H, 9.22; N, 3.57; I, 32.26. Found: C, 54.89; H, 9.10; N, 3.60; I, 33.01.

The above product was tested with the following results:

EXAMPLE VI 3-decyl-3-azabicyclo[3.2.2]nonane hydrobromide To a solution of 10 g. (0.0376 mole) of 3-decyl-3-azabicyclo[3.2.2]nonane in 350 ml. of absolute ethanol was added 3.2 g. (0.0376 mole) of 48% hydrobromic acid. The resulting solution was chilled in the refrigerator for two days. No solid resulted and 700 ml. of anhydrous ethyl ether was added to the solution which was chilled overnight in the refrigerator.

A solid product was obtained by filtration. The solid was dried at 60 C. to obtain 2.8 g., M.P. 249-250 C. (d.). Recrystallization from ethanol-ether yielded a pure product, 3-decyl-3-azabicyclo[3.2.2]nonane hydrobromide, 1.3 g., M.P. 250-252 C. (d.).

Analysis.Calcd for C18H36BIN1 C, 62.41; H, 10.48; N, 4.04; Br, 23.07. Found: C, 62.52; H, 10.24; N, 4.14; Br, 23.52.

3-decyl-3-azabicyclo[3.2.2]nonane hydrobromide was tested with the following results:

EXAMPLE V-II 3-decyl-3-azabicyclo[3.2.2]nonane hydrogen oxalate A solution of 10 g. (0.038 mole) of 3-decyl-3-azabicyclo[3.2.2]nonane in ml. of anhydrous ethyl ether was added to a filtered solution of 3.4 g. (0.038 mole) of oxalic acid in 200 ml. of anhydrous ethyl ether. A white solid formed and the mixture was refrigerated overnight.

The solid was separated by filtration and dried at 60 C. The product, 12.8 g., M.P. -157 C., was recrystallized from benzene-hexane to obtain 11.9 g. of pure product, 3-decyl-3-azabicyclo[3.2.2]nonane hydrogen oxalate, M.P. 156-157 C.

Analysis.Calcd for C H NO C, 67.57; H, 10.49; N, 3.94. Found: C, 67.66; H, 10.71; N, 3.75.

This compound was tested with the following results:

EXAMPLE VIII 3-decyl-3-azabicyclo[3.2.2]nonane hydrogen maleate A solution of 10 g. (0.038 mole) of 3-decyl-3-azabicyclo[3.2.2]nonane in 100 ml. of anhydrous ethyl ether was added to a solution of 4.4 g. (0.038 mole) of maleic acid in 250 ml. of anhydrous ethyl ether. A white solid formed and the mixture was refrigerated overnight.

Killing time Organism: in minutes S. aureus ,1 -10 Str. pyogenes 5-10 D. pneumoniae J 1-5 E. coli 5-10 Ps. aeruginosa 1-5 Sal. choleraesuis 1-5 EXAMPLE IX 3-decyl-3-azabicyclo[3.2.2]nonane hydrogen tartrate A solution of g. (0.0376 mole) of 3-decy1-3-azabicyclo[3.2.2]nonane in 50 ml. of anhydrous ethyl ether was added to a solution of 5.7 g. (0.0376 mole) of d-tartaric acid in 400 ml. of anhydrous ethyl ether.

The mixture was refrigerated overnight. A white, solid product was filtered and dried at 60 C. to obtain 1.4 g. of material, M.P. 84-86 C. Recrystallization of the solid from chloroform-hexane yielded 0.9 g. of pure product, 3-decyl-3-azabicyclo[3.2.2]nonane hydrogen tartrate, M.P. 85-87 C.

Analysis.-Calcd for C H NO C, 63.58; H, 9.95; N, 3.67. Found: C, 69.23; H, 10.51; N, 3.40.

This compound was tested and gave the following results:

3-decyl-3-azabicyclo[3.2.2]nonane To a mixture of 85.3 g. (0.289 mole) of 3-decy1-3- azabicyc1o[3.2.2]nonane hydrochloride in 400 ml. of water was added 32 ml. (0.32 mole) of 10 N sodium hydroxide solution with vigorous stirring. The product was separated from the resulting alkaline mixture by a procedure identical to the one used to isolate 3-octyl-3- azabicyc1o[3.2.2]nonane.

The oil was distilled under reduced pressure to obtain 17.4 g. of a clear, colorless oil, B.P. at 0.4 mm. of mercury, 131-133 C.; N 1.4760, which was pure 3-decyl- 3-azabicyclo[3.2.2]nonane.

Analysis.Calcd for C H N: C, 81.44; H, 13.29; N, 5.28. Found: C, 81.64; H, 13.29; N, 5.30.

EXAMPLE XI 3-decyl-3-methyl-3-azoniabicyclo [3 .2.2] nonane iodide A mixture of 4 g. (0.0151 mole) of 3-decyl-3-azabicyclo[3.2.2]nonane, 10.7 g. (0.0604 mole) of methyl iodide and 150 ml. of methanol was heated to reflux. The mixture was cooled to room temperature, concentrated to one-half of the original volume and 500 ml. of anhydrous diethyl ether were added to the concentrate. Upon chilling the mixture overnight in the refrigerator, a white solid formed. The solid was separated by filtration.

Recrystallization of the white solid from dry acetonedry hexane, absolute ethanol-absolute ether, dry acetonedry hexane and twice more from acetone-ethyl acetate yielded 0.3 g. of analytically pure product, 3-decyl-3- 8 methyl-3-azoniabicyclo[3.2.21nonane iodide, M.P. 220- 221 C. ((1.).

Analysis.-Calcd for C H IN: C, 56.01; H, 9.40; N, 3.44; I, 31.15. Found: C, 56.03; H, 9.18; N, 3.26; I, 31.38.

EXAMPLE XII 3-dodecyl-3-azabicyclo[3.2.2]nonane hydrochloride A mixture consisting of 12.52 g. (0.1 mole) of 3-azabicyclo[3.2.2]nonane, 24.92 g. (0.1 mole) of l-bromododecane and 5.3 g. (0.05 mole) of anhydrous sodium carbonate in 150 ml. of dry benzene was stirred under reflux for seven hours. The cooled reaction mixture was filtered and the benzene was distilled from the filtrate under reduced pressure. The yellow oil, which was obtained as a residue, was stirred into ml. of 3 N hydrochloric acid. A solid which formed was filtered and dried at 60 C. The solid weighed 11.4 g., M.P. 231237 C. Recrystallization from absolute alcohol-ether and then two times from tertiary butyl alcohol yielded a solid, 3.0 g., M.P. 231- 234" C., which was the pure product, 3-dodecyl-3-azabicyclo 3.2.2] nonane hydrochloride.

Analysis.-Calcd for C H C1N: C, 72.79; H, 12.22; N, 4.25. Found: C, 72.57; H, 12.04; N, 4.12.

EXAMPLE XIII 3-dodecyl-3-azabicyclo [3 .2.2] nonane To a mixture of 84.1 g. (0.255 mole) of 3-dodecyl-3- azabicyclo[3.2.2]nonane hydrochloride in 400 ml. of water was added 28 ml. (0.28 mole) of 10 N sodium hydroxide solution with vigorous stirring. The product was separated from the resulting alkaline mixture by a procedure identical to the one used to isolate 3-octyl-3-azabicyclo [3.2.2] nonane.

The oil was distilled under reduced pressure to obtain 53.2 g. of a colorless, cloudy oil, B.P. at 0.4 mm. of mercury, 171-176 C.; N 1.4759, which was pure 3- dodecyl-3-azabicyclo [3.2.2] nonane.

Analysis.-Calcd for C H N: C, 81.84; H, 13.39; N, 4.77. Found: C, 81.94; H, 13.10; N, 4.79.

EXAMPLE XIV 3-dodecyl-3-methyl-3-azoniabicyclo[3.2.2]nonane iodide analytically pure product, 3-dodecyl-3-methyl-3-azoniabicyclo[3.2.2]nonane iodide, M.P. 225-227 C.

Analysis.Calcd for C H IN: C, 57.92; H, 9.72; N,

3.22; I, 29.14. Found: C, 57.67; H, 9.73; N, 3.35; I, 28.94. 3 dodecyl 3 methyl-3-azoniabicyclo[3.2.2]nonane iodide was tested and the following results obtained:

Organism: Killing time in minutes S. aureus 1 Str. pyogenes 1 D. pneumoniae 1 E. coli 1 Ps. aeruginosa 1-5 Sal. choleraesuis 1-5 C. albz'cans 1 T. interdigitale 1 EXAMPLE XV 3-tetradecyl-3-azabicyclo[3.2.2]nonane hydrochloride A mixture consisting of 12.52 g. (0.1 mole) of 3-azabicyclo[3.2.2]nonane, 27.72 g. (0.1 mole) of 1-bromotetradecane and 5.3 g. (0.05 mole) of anhydrous sodium carbonate in 150 ml. of absolute ethanol was stirred under reflux for 48 hours. The solvent had evaporated during this time. An additional 100 ml. of absolute ethanol were added and an orange solution containing some solid was obtained. The suspension was filtered and the solvent was distilled from the filtrate under reduced pressure to obtain a residue of oil and solid.

The residue was stirred in 200 ml. of diethyl ether and the insoluble solid was removed by filtration. The filtrate, after dilution by the addition of 250 ml. of ether, was acidified by the addition of 15 ml. of a 7.4 N solution of hydrogen chloride in absolute ethanol with stirring and ice-bath chilling.

After the addition of 100 ml. of ether, the cloudy suspension was cooled under refrigeration and a solid resulted.

The orange-white solid was filtered and dried at 60 C. to obtain 21.21 g. of crude product. The pure 3-tetradecyl-3-azabicyclo[3.2.2]nonane hydrochloride was obtained, after three recrystallizations from water, as a white solid, 10.3 g., M.P. 238-240 C. (d).

Analysis.-Calcd for C H 4ClN: C, 73.80; H, 12.39; N, 3.91. Found: C, 73.74; H, 12.31; N, 4.08.

EXAMPLE XVI 3-tetradecyl-3 -azabicyclo [3 .2.2] nonane To a mixture of 78.2 g. (0.217 mole) of 3-tetradecyl- 3-azabicyclo[3.2.2]nonane hydrochloride in 400 ml. of water was added 24 ml. of (0.24 mole) of 10 N sodium hydroxide solution with vigorous stirring. The product was separated from the resulting alkaline mixture by a procedure identical to the one used to isolate 3-octyl-3- azabicyclo[3.2.2]nonane.

The oil was distilled under reduced pressure to obtain 52.5 g. of a clear, colorless oil, BJP. at 0.3 mm. of mercury, 160-161 C.; N 1.4750, which was pure 3-tetradecyl- 3-azabicyclo[3.2.2]nonane.

Analysis.-Calcd for C H N: C, 82.17; H, 13.48; N, 4.36. Found: C, 81.99; H, 13.51; N, 4.58.

EXAMPLE XVII 3-methyl-3-tetradecyl-3-azoniabicyclo[3.2.2]nonane iodide A mixture of 13.9 g. (0.0433 mole) of 3-tetradecyl-3- azabicyclo[3.2.2]nonane, 30.70 g. (0.163 mole) of methly iodide and 75 ml. of methanol was heated under reflux for approximately 60 hours. An additional 12 g. (0.0849 mole) of methyl iodide was added to the mixture and the entire mixture was heated under reflux for 24 hours longer. The reaction mixture was concentrated to one-half of the final volume and 350 ml. of anhydrous diethyl ether were added and a white solid separated. The white solid was filtered by suction after the mixture had been chilled overnight. The product, a white solid, weighed 14.9 g. and had a melting point of 214218 C.

A 2 g. sample of the product was recrystallized from ethyl acetate and finally from chloroform-ether to obtain 0.3 g. of analytically pure product, 3-methyl-3-tetradecyl- 3-azoniabicyclo[3.2.2]nonane iodide, M.P. 216-217 C.

Analysis.Calcd for C H IN: C, 59.59; H, 10.01; N, 3.02; I, 27.38. Found: C, 59.69; H, 10.09; N, 3.21; I, 27.10.

3-methyl-3-tetradecyl 3 azoniabicyclo[3.2.2]nonane iodide was tested with the following results:

10 EXAMPLE XVIII 3-(3-chloro-5-fluoro-2-hydroxybenzyl)-3-azabicyclo [3.2.2]nonane hydrochloride A solution of 20 g. (0.150 mole) of 2-chloro-4-fluorophenol and 23.64 g. (0.188 mole) of 3-azabicyclo[3.2.2] nonane in 350 ml. of methanol was filtered by gravity into a flask which was equipped with a thermometer, stirrer, condenser and dropping funnel. To the filtered solution was added, dropwise with stirring starting at a temperature of 35 C., 15.23 g. (0.188 mole) of formaldehyde as a 35-40% aqueous solution. During the addition the temperature of the solution rose 4 C.

After the addition was completed, the mixture was stirred at room temperature for one hour and stirred under reflux for two hours. After two hours of stirring under reflux, the reaction mixture was allowed to stand at room temperature for 102 hours.

The solvent was distilled from the reaction mixture under reduced pressure at 60 C. The oily residue which was obtained was shaken with ml. of 3 N hydrochloric acid. Then, 100 m1. of water and 50 ml. of methanol were added and shaken with the acid mixture. This mixture was treated with three 100 ml. portions of ethyl ether and a white solid formed. The suspension was filtered under suction and the solid which was obtained was dried at 60 C. The dried solid weighed 8.02 g., M.P. 215220 C. A second quantity of solid, which weighed 1.17 g., M.P. 216 22l C., was obtained from the filtrate and was combined with the first solid.

The combined solids were recrystallized from absolute ethanol and 3.92 g. of pure product, 3-(3-chloro-5-fluoro- 2-hydroxybenzyl)-3-azabicyclo[3.2.2]nonane hydrochloride, M.P. 226-228" C., were obtained.

Analysis.-Calcd for C H Cl FNO: C, 56.26; H, 6.30; N, 4.38. Found: C, 56.25; H, 6.30; N, 4.40.

3-(3-chloro-5-fluoro-2-hydroxybenzyl) 3 azabicyclo [3.2.2]nonane hydrochloride was tested with the following results:

EXAMPLE XIX 3- 3-chloro-5-fluoro-2-hydroxybenzyl -3 -azabicyclo [3.2.2]nonane hydrobromide To a filtered solution of 10 g. (0.035 mole) of 3-(3- chloro-5-fluoro-2-hydroxybenzyl) 3 4 azabicyclo[3.2.2] nonane in 850 ml. of absolute ethanol was added 2.8 g. (0.035 mole) of 48 hydrobromic acid. The solution was stirred and chilled in the refrigerator overnight. No product formed.

The solution was concentrated to approximately ml. and chilled. A pure product formed and after filtration and drying at 60 C., weighed 4.0 g., M.P. 197-199 C. This was 3-(3-chloro-5-fluoro-2-hydroxybenzyl)-3- azabicyclo[3.2.2]nonane hydrobromide.

Analysis.Calcd for C H BrClFNO: C, 49.40; H, 5.53; N, 3.84; Br, 21.91. Found: C, 49.42; H, 5.55; N, 4.05; Br, 21.66.

. EXAMPLE XX 3-(3-chloro-S-fluoro-Z-hydroxybenzyl)-3-azabicyclo- [3.2.2]nonane hydroiodide To a filtered solution of 10 g. (0.035 mole) of 3-(3- chloro-S-fluoro-Z-hydroxybenzyl) 3 azabicyclo[3.2.2] nonane in 850 ml. of absolute ethanol was added 4.5 g. (0.035 mole) of 57% hydroiodic acid. 1

The procedure was essentially the same as that used in Example XIX. 7.7 g. of pure product, 3-(3-chloro-5- fluoro 2 hydroxybenzyl) 3-azabicyclo[3.2.2]nonane hydroiodide, was obtained.

Analysis.-Calcd for C H ClFINO: C, 43.76; H, 4.90; N, 3.40; I, 30.83. Found: C, 43.74; H, 5.11; N, 3.52; I, 31.00.

3 (3 chloro-5-fiuoro-2-hydroxybenzyl)-3-azabicyclo- [3.2.2]nonane hydroiodide was tested with the following results:

Organism: Killing time in minutes S. aureus 5-10 Sir. pyogenes 1-5 D. pneumoniae 1-5 E. coil 10 Ps. aeruginosa 10 Sal. choleraesuis 5-10 EXAMPLE XXI 3-(3-chloro-5-fiuoro-2-hydroxybenzyl)-3-azabicyclo- [3.2.2] nonane hydrogen oxalate EXAMPLE XXII 3-(3-chloro-S-fluoro-Z-hydroxybenzyl)-3-azabicyclo- [3 .2.2]nonane hydrogen maleate To a filtered solution of 4.1 g. (0.035 mole) of maleic acid in 350 ml. of anhydrous ethyl ether was added a filtered solution of 3-(3-chloro-5-fluoro-2-hydroxybenzyl)- 3-azabicyclo[3.2.2]nonane in 450 ml. of anhydrous ethyl ether. The mixture was refrigerated overnight.

The white solid which had formed was filtered and dried at 60 C. to obtain a pure product, 3-(3-chloro-5- fluoro 2 hydroxybenzyl)-3-azabicyclo[3.2.2] nonane hydrogen maleate, 9.4 g., M.P. 147-149 C.

Analysis.-Calcd for C H Cl FNO C, 57.07; H, 5.80; N, 3.50. Found: C, 57.20; H, 6.03; N, 3.43.

EXAMPLE XXIII 3-(3-ch1or0-5-fluoro-2-hydroxybenzyl)-3-azabicyclo- [3.2.2]nonane monohydrogen sulfate A mixture of 4 g. (0.0141 mole) of 3-(3-chloro-5- fluoro 2 hydroxybenzyl)-3-azabicyclo[3.2.2]nonane, 50 ml. of distilled water and 1.39 g. (0.0141 mole) of concentrated sulfuric acid was stirred for two hours. To the resulting suspension, 100 ml. of 1,4-dioxane were added and the clear solution which resulted was filtered. The solvent was distilled from the filtrate under reduced pressure and 100 ml. of water were added to the distillation residue. The resulting solution was filtered and the water was distilled from the filtrate under reduced pressure, once again.

The distillation residue was recrystallized once from absolute ethanol diethyl ether, twice from dry acetone, and once more from ethanol-ether to obtain 0.3 g. of pure product, 3-(3-chloro-5-fiuoro-2-hydroxybenzyl)-3- azabicyclo[3.2.2]nonane monohydrogen sulfate, M.P. 154-155 C.

Analysis.-Calcd for C H ClF N 5: C, 47.17; H, 5.54; N, 3.67. Found: C, 47.13; H, 5.64; N, 3.62.

12 EXAMPLE XXIV 3 3-benzyl5-chloro-2-hydroxybenzyl) -3 -methyl-3- azoniabicyclo[3.2.2]nonane methosulfate A mixture of 6 g. (0.0169 mole) of 3-(3-benzyl-5- chloro 2 hydroxybenzyl)-3-azabicyclo[3.2.2]nonane, 2.35 g. (0.0186 mole) of dimethyl sulfate and 150 ml. of methanol was heated to the reflux temperature. An additional 2.35 g. (0.0186 mole) of dimethyl sulfate were added to the hot reaction mixture. The mixture was left cool and a white solid formed.

The solid was separated by filtration and recrystallized from methanol and finally from methanol-ether to obtain a white solid, 2.0 g., M.P. 196 C. (d.), which was analytically pure 3-(3-benzyl-5-chloro-2-hydroxybenzyl)- 3-methyl-3-azoniabicyclo[3.2.2]nonane methosulfate.

Analysis.Calcd for C H ClN0 S: C, 59.79; H, 6.69; N, 2.91. FoundzC, 59.21; H, 6.48; N, 2.70.

EXAMPLE XXV 3- (5 -chloro-3-cyclopentyl-Z-hydroxybenzyl) -3azabicyclo[ 3 .2.2] nonane hydrochloride A solution of 25 g. (0.127 mole) of 4-chloro-2-cyc1opentylphenol, 19.03 g. (0.152 mole) of 3-azabicyclo [3.2.2]nonane and 11.4 ml. (0.152 mole) of a 37% aqueous solution of formaldehyde in 300 ml. of methanol was stirred. The procedure which was used was essentially the same as the one used to prepare 3-(3,5-dichloro-2- hydroxybenzyl) 3 azabicyclo[3.2.2]nonane hydrochloride.

Recrystallization of the products from ethanol and water yielded 21.8 g., M.P. 233-235 C., of pure 3-(5- chloro-3-cyclopentyl-2-hydroxybenzyl) 3 azabicyclo [3.2.2] nonane hydrochloride.

Analysis.-Calcd for CZOHZQCIQNOZ C, 64.86; H, 7.89; N, 3.78. Found: C, 64.94; H, 7.97; N, 3.90.

EXAMPLE XXVI 3- (5-chloro-3-cyclopentyI-Z-hydroxybenzyl) -3-azabicyclo [3.2.2] nonane To a suspension of 88.3 g. (0.237 mole) of 3-(5-chloro- 3-cyclopentyl-Z-hydroxybenzyl) 3 azabicyclo[3.2.2] nonane hydrochloride in 600 ml. of 50% aqueous dimethylformamide was added 320 ml. of a saturated aqueous solution of sodium bicarbonate. The crude prodnot was isolated by a procedure similar to that used for 3-(3,5-dichloro-2-hydroxybenzyl) 3 azabicyclo[3.2.2] nonane. After the product was recrystallized from absolute ethanol and finally from hexane, the pure 3-(5-chloro-3- cyclopentyl-Z-hydroxybenzyl) 3 azabicyclo[3.2.2]nonane was obtained as tan crystals, M.P. 86-89 C.

Analysis.-Calcd for C H ClNO: C, 71.94; H, 8.45; N, 4.19. Found: C, 72.07; H, 8.41; N, 4.24.

EXAMPLE XXVII 3- 5-chloro-3 -cyclopentyl-2-hydroxyben zyl -3-methyl- 3-azoniabicyclo [3 .2.2]nonane methosulfate A mixture of 2 g. (0.00599 mole) of 3-(5-chloro-3- cyclopentyl-2-hydroxybenzyl) 3 azabicyclo[3.2.2]nonane, 3.78 g. (0.0240 mole) of dimethyl sulfate and ml. of methanol were heated under reflux for 48 hours. The reaction mixture was cooled to room temperature and 500 ml. of anhydrous diethyl ether were added. Upon chilling the mixture, 21 white solid separated in small amounts. Filtration removed the White solid and 35 0 ml. of ether were added to the filtrate and the mixture was chilled.

A white solid formed and was filtered by suction to obtain 0.7 g. of product 3-(5-chloro-3-cyclopentyl-2-hydroxybenzyl)-3-methyl 3 azoniabicyclo[3.2.2]nonane methosulfate, M.P. 168170 C., which was analytically pure.

Analysis.-Calcd for C H ClNO S: C, 57.44; H, 7.45; N, 3.05. Found: C, 56.99; H, 7.37; N, 3.07.

13 EXAMPLE XXV-III 3- (2-hydroxy-3,5,6-trichlorobenzyl '-3-azabicyclo ['3 .2.2] nonane hydrochloride A solution of 39.5 g. (0.2 mole) of 2,4,5-trichlorophenol and 31.7 g. (0.253 mole) of 3-azabicyclo[3.2.2] nonane in 35 ml. of methanol was filtered by gravity into a flask which was equipped with a thermometer, stirrer, condenser and dropping funnel. To the filtered solution was added, dropwise with stirring, 20.6 g. (0.253 mole) of 35-40% aqueous formaldehyde solution. The addition required five minutes and the internal temperature rose 3 C.

After the addition was completed, the mixture was stirred at room temperature for one hour and stirred under reflux for two hours. After two hours of stirring under reflux, the reaction mixture was allowed to stand at room temperature overnight.

The solvent and water were distilled from the reaction mixture under reduced pressure at 4050 C. The residue, a brown gum, was shaken with 100 m1. of 3 N hydrochloric acid. Then, 50 ml. of methanol and 100 m1. of water were added and the acid mixture was shaken. This mixture, which consisted of two liquid layers, was extracted with two 100 ml. portions of ethyl ether and a white solid formed. The suspension was filtered under suction and the solid which was obtained was dried at 60 C. The dried solid weighed 14.8 g., M.P. 193-195 C.

The crude solid was purified by recrystallization from absolute ethanol and after three recrystallizatious 3.21 g. of pure product, 3-(2-hydroxy-3,5,6-trichlorobenzyl)-3- azabicyclo[3.2.2]nonane hydrochloride, M.P. 210-213 C. were obtained.

Analysis.Calcd for C H Cl N0: C, 48.54; H, 5.16; N, 3.78. Found: C, 49.06; H, 5.24; N, 3.65.

3-(2-hydroxy-3,5,6-trichlorobenzyl) 3 azabicyclo [3.2.2]nonane hydrochloride was tested and the results obtained were as follows:

EXAMPLE XXIX 3-(2-hydroxy-3,5,6-trichl'orobenzyl)-3 -azabicyclo [3 .2.2] nonane hydrobromide To a solution of g. (0.03 mole) of 3-(2 hydroxy- 3,5,6-trichlorobenzyl)-3-azabicyclo[3.2.2]nonane in 500 ml. of absolute ethanol was added 5.1 g. (0.03 mole) of 48% hydrobromic acid. The solution was refrigerated for three days. No solid resulted. The alcohol and water was distilled under reduced pressure and a white solid, 8.3 g., was obtained.

The solid was recrystallized twice from chloroformhexane and 6.1 g. of pure product, 3-(2-hydroxy-3,5,6- trichlorobenzyl) 3 azabicyclo[3.2.2]nonane hydrobromide, M.P. 205-206 C. were obtained.

Analysis.Calcd for C H BrCl NO: C, 43.35; H, 4.61; N, 3.37; Br, 19.23. Found: C, 43.32; H, 4.63; N, 3.29; Br, 19.04.

The compound was tested with the following results:

14 EXAMPLE XXX 3-(Z-hydroxy-3,5,6-trichlorobenzyl)-3-azabicyclo [3 .2.2] nonane hydroiodide To a filtered solution of 10 g. (0.03 mole) of 3-(2-hydroxy-3,5,6-trichlorobenzyl) 3 azabicyclo[3.2.2]nonane in 350 ml. of ethanol was added 9 g. (0.03 mole) of 57% aqueous hydroiodic acid with stirring. The solution was chilled in the refrigerator overnight.

A white solid which had formed was filtered and dried at 60 C. to obtain a product, 7.9 g., M.P. 2102l1 C. (d.). This product was purified by recrystallization from methanol-water and finaly twice from absolute ethanol to obtain an analytically pure product, 3-(2-hydroxy- 3,5,6 trichlorobenzyl)-3-azabicyclo[3.2.2]nonane hydroiodide, 4.6 g., M.P. 2112l2 C. (d.).

Analysis.Calcd for C H Cl IN0: C, 38.94; H, 4.14; N, 3.03; I, 27,44. Found: C, 38.88; H, 4.35; N, 2.92; I, 27.41.

1 3-(2-hydroxy 3,5,6 trichlorobenzyl) 3 azabicyclo [3.2.2]nonane hydroiodide was tested with the following results:

Organism: Killing time in minutes S. aureus 1 Str. pyogenes 1 D. pneumoniae 1 E. coli 1-5 Ps. aeruginosa 1-5 Sal. choleraesuis 1-5 C. albicans 1 T. interdigitale 1 EXAMPLE XXXI 3-(2-hydr0xy-3,5,6-trichlorobenzyl)-3-azabicyclo[3 .2.2]nonane hydrogen maleate To a solution of 10 g. (0.03 mole) of 3-(2-hydroxy- 3,5,6 trichlorobenzyl)-3-azabicyclo[3.2.2]nonane in 500 ml. of anhydrous ethyl ether was added a solution of 3.5 g. (0.03 mole) of maleic acid in 300 ml. of anhydrous ethyl ether with stirring. The mixture was refrigerated overnight.

The solid which had formed was filtered and dried at 60 C. The product, 8.7 g., M.P. -142 C., was purified by recrystallization from chloroform-hexane and the solid which formed on cooling was filtered yielding an analytically pure product, 3-(2-hydroxy-3,5,6-trichlorobenzyl)-3-azabicyclo[3.2.2] nonane hydrogen maleate, 7.0 g., M.P. 138139 C.

Analysis.Calcd for C H Cl NO C, 50.62; H, 4.92; N, 3.11. Found; C, 50.44; H, 5.15; N, 2.97.

3-(2-hydroxy 3,5,6 trichlorobenzyl) 3 azabicyclo [3.2.2]nonane hydrogen maleate was tested with the following results:

3- (2-hydroxy3,5,6-trichlorobenzyl) -3-azabicyclo [3 .2.2] nonane hydrogen oxalate monohydrate To a filtered solution of 3.8 g. (0.03 mole) of oxalic acid in 100 ml. of anhydrous ethyl ether was added, with stirring, a filtered solution of 10 g. (0.03 mole) of 3-(2-hydroxy-3,5,6-trichlorobenzyl) 3 azabicyclo[3.2.2]nonane in 250 ml. of anhydrous ethyl ether. A white solid separated. The mixture was refrigerated for three days. The solid product, 10.0 g., M.P. 171 C. (d.), was filtered and dried at 60 C.

Organism: Killing time in minutes S. aureus -10 Str. pyogenes D. pneumoniae 5-10 E. coli 5-10 Ps. aeruginosa 5-10 Sal. choleraesuz's 1-5 EXAMPLE xxxrn 3-(2-hydroxy-3,5,6-trichlorobenzyl)-3-azabicyclo[3.2.2]

nonane To a stirred suspension of 31.4 g. (0.0846 mole) of 3-(2-hydroxy 3,5,6 trichlorobenzyl) 3 azabicyclo [3.2.2]nonane hydrochloride in 200 ml. of 50% dimethylformamide was added 100 ml. of pure dimethylformamide and the mixture was warmed to facilitate solution. To the resulting warm solution was added with stirring 125 ml. of a saturated solution of sodium bicarbonate. A white solid formed and the stirred suspension was allowed to cool to room temperature.

A white solid separated from the alkaline mixture. The product was isolated in a manner similar to the one used to isolate 3-(3,5-dichloro-2-hydroxybenzyl)-3-azabicyclo [3.2.2] nonane.

The solid was recrystallized from absolute ethanol and the product, 37.9 g., M.P. 9698 C., was isolated as pure 3-(3-benzyl-5-chloro 2 .hydroxybenzyl)-3-azabicyclo [3.2.2]nonane.

Analysis.Calcd for C H ClNO: C, 74.24; H, 7.37; N, 3.94. Found: C, 73.90; H, 7.50; N, 3.94.

EXAMPLE XXXIV 3-methyl-3-(2-hydroxy-3,5,6-trichlorobenzy1)-3-azoniabicyclo[3.2.2]nonane iodide Following the procedure of Example III, the compound 3-(2 hydroxy-3,5,6-trichlorobenzyl)-3-azabicyclo[3.2.2] nonane can be reacted with methyl iodide to yield 3- methyl-3-(2-hydroxy 3,5,6 trichlorobenzyl)-3-azoniabicyclo[3.2.2]nonane iodide or else with other alkyl halides to yield the desired quaternary ammonium salt.

EXAMPLE XXXV 3-(3,5-dichloro-2-hydroxybenzyl)-3-azabicyclo[3.2.2] nonane hydrochloride A solution of 25 g. (0.153 mole) of 2,4-dichlorophenol and 24.29 g. (0.194 mole) of 3-azabicyclo[3.2.2]nonane in 300 ml. of methanol was filtered by gravity into a flask which was equipped with a thermometer, stirrer, condenser and dropping funnel. To the filtered solution at 37 C. was added, dropwise with stirring, 14.6 g. (.0194 mole of 35-40% aqueous formaldehyde solution. The internal temperature of the mixture was 40 C. after the addition was completed.

After the addition of the formaldehyde was completed, the mixture was stirred at room temperature for one hour and then stirred under reflux for two hours. After two hours of stirring under reflux, the reaction mixture was allowed to stand at room temperature for 94 hours.

The solvent and water were distilled from the reaction mixture under reduced pressure at 50 C. The residue, a brown oil, was shaken with 100 ml. of 3 N hydrochloric acid and 100 ml. of water were added to the acid mixture, and the whole mass was mixed by shaking. The resulting liquid suspension was extracted with three 100 ml. portions of ethyl ether and a solid formed. The suspended solid was filtered under suction and the solid which was 16 obtained was dried at 60 C. The dried solid weighed 14.5 g. M.P. 208-212 C.

The solid was recrystallized from absolute ethanol and after two recrystallizations 6.01 g. of pure product, 3- (3,5-dichloro-2-hydroxybenzyl) 3 azabicyclo[3.2.2] nonane hydrochloride, M.P. 222-224 C., were obtained.

Analysis.-Caled for C H CI NO: C, 53.50; H, 5.98; N, 4.18. Found: C, 53.78; H, 5.91; N, 3.91.

3-(3,S-dichloro-2-hydroxybenzyl) 3 azabicyclo[3.2.2] nonane hydrochloride was tested with the results obtained as follows:

Organism: Killing time in minutes S. aureus 10 Str. pyagenes 10 D. pneumoniae E. coli 1-5 Ps. aeruginosa 5-10 Sal. choleraesuis 1-5 C. albicans 1 T. interdigitale 1 EXAMPLE XXXVI 3- (3,5 -dich1oro-2-hydroxybenzyl) -3 -azabicyclo [3 .2.2] nonane hydroiodide To a solution of 10 g. (0.032 mole) of 3-(3,5-dichloro- 2 hydroxybenzyl) 3 azabicyclo[3.2.2]nonane in 900 ml. of absolute ethanol was added 4.1 g. (0.032 mole) of 57% hydroiodic acid and the resulting solution was chilled in the refrigerator for six days.

The ethanol and water was distilled under reduced pressure to obtain 17.7 g. of white solid. After recrystallization from ethanol-hexane and, finally, chloroformhexane a pure produce, 3-(3,5-dichloro 2 hydroxybenzyl)- 3-azabicyclo[3.2.2]nonane hydroiodide, 3.2 g., M.P. 189- 190" was obtained.

Analysis.-Calcd for C H Cl INO: C, 42.08; H, 4.71; N, 3.27; I, 29.64. Found: C, 42.19; H, 4.70; N, 3.34; I, 29.92.

EXAMPLE XXXVII 3- 3 ,5 -dichloro -2-hydroxyb enzyl) -3*azabicyclo [3.2.2]nonane hydrobromide To a filtered solution of 10 g. (0.032 mole) of 3-(3,5- dichloro-2-hydroxybenzyl) 3 azabicyclo[3.2.2]nonane in 900 ml. of absolute ethanol was added 2.6 g. (0.032 mole) of 48% hydrobromic acid. The resulting solution was chilled. No product separated.

The alcohol and water was distilled under reduced pressure and the residue dried at 60 C. to obtain 8.6 g. of product, M.P. 206-207 C. Two recrystallizations from ethanol-ether yielded 3.0 g. of pure product, 3-(3,5-dichloro-2-hydroxybenzy1) 3 azabicyclo[3.2.2]nonane hydrobromide, M.P. 214-215 C.

Analysis.-Calcd for c, H,,Brc1,No= C, 47.26; H, 5.29; N, 3.68. Found: C, 47.23; H, 5.51; N, 3.76.

EXAMPLE XXXVIII 3-(3,5-dich1oro-2-hydroxybenzy1)-3-azabicyc1o [3.2.2]nonane hydrogen oxalate A solution of 10 g. (0.032 mole) of 3-(3,5-dichloro- 2 hydroxybenzyl) 3 azabicyclo[3.2.2]nonane in 500 ml. of anhydrous ethyl ether was filtered into a solution of 2.9 g. (0.032 mole) of oxalic acid in 250 ml. of anhydrous ethyl ether and the mixture was refrigerated overnight.

The white solid which had formed was filtered and dried at 60 C. to obtain 9.8 g. of product, 3-(3,5-dichloro- Z-hydroxybenzyl) 3 azabicyclo[3.2.2]nonane hydrogen oxalate, M.P. 147-150 C.

Analysis.Calcd for C H Cl NO C, 52.31; H, 5.42; N, 3.59. Found: C, 52.31; H, 5.36; N, 3.59.

This compound was tested with the following results:

3- (3 ,5 -dichloro-2-hydroxybenzyl) -3-azabicyclo [3.2.2]nonane To a Warm solution of 35.2 g. (0.105 mole) of 3-(3,5- dichloro 2 hydroxybenzyl) -3-azabicyclo[3.2.2]nonane hydrochloride in 50% dimethylformamide was added 125 ml. of a saturated solution of sodium bicarbonate with stirring. A white solid separated from the alkaline mixture. The suspension was cooled to room temperature and extracted with four 100 ml. portions of diethyl ether. The combined ether extracts were dried by means of anhydrous sodium sulfate. The ether was distilled under reduced pressure and a white, solid residue, 31.9 g., M.P. 99103 C., was obtained. Two recrystallizations of the product from absolute ethanol yielded 20.5 g. of the pure product, 3-(3,5-dichloro 2 hydroxybenzyl)-3-azabicyclo[3.2.2]nonane, M.P. 114-115 C.

Analysis.Calcd for C I-I Cl NO: C, 60.00; H, 6.38; N, 4.67. Found: C, 60.18; H, 6.51; N, 4.77.

EXAMPLE XL 3 -ethyl-3 3 ,5 -dichloro-2-hydroxyb enzyl) -3- azoniabicyclo[3.2.2]nonane chloride Following the procedure of Example HI, the compound 3-(3,5-dichloro 2 hydroxybenzyl)-3-azabicyclo[3.2.2] nonane can be reacted with ethyl chloride to yield 3-ethyl- 3-(3,5-dichloro 2 hydroxybenzyl) 3 azoniabicyclo [3.2.2]nonane chloride.

EXAMPLE XLI 3-(3-benzy1-5 -chloro-2-hydroxybenzy1)-3-azabicyclo [3.2.2] nonane hydrochloride A solution of 25 g. (0.114 mole) of 2-benzyl-4-chlorophenol, 17.15 g. (0.137 mole) of 3 azabicyclo[3.2.2] nonane and 10.2 ml. (0.137 mole) of a 37% aqueous solution of formaldehyde in 300 ml. of methanol was stirred. The reaction conditions and procedure which were used to prepare this product are essentially the same as those used to prepare 3-(3,5-dichloro 2 hydroxybenzyl)-3-azabicyclo[3.2.2]nonane hydrochloride.

The crude, white solid which was isolated, 29.8 g., M.P. 213-217 C., was recrystallized from water and ethanol to obtain 22.6 g. of pure product, 3-(3-benzyl- 5-chloro-2-hydr0xybcnzyl) 3 azabicyclo[3.2.2]nonane hydrochloride, M.P. 2l3216 C.

Analysis.Calcd for C H Cl NO: C, 67.17; H, 6.92; N, 3.56. Found: C, 67.32; H, 7.00; N, 3.69.

EXAMPLE XLII 3- (3-b enzyl-5-chloro-2-hydroxybenzyl) -3-azabicyclo [3.2.2]nonane To a warm solution of 79.0 g. (0.222 mole) of 3-(3- benzyl 5 chloro 2-hydroxybenzyl)-3-azabicyclo[3.2.2] nonane hydrochloride in 50% aqueous dimethylformamide was added 294 ml. of a saturated aqueous solution of sodium bicarbonate with stirring. The cool suspension was extracted with four 100 ml. portions of diethyl ether and the combined ether extracts were dried over anhydrous sodium sulfate. After filtration of the dried ether solution, the ether was distilled under reduced pressure and 38.1 g. of a white solid resulted. The solid was recrystallized twice from absolute ethanol and 22.7 g. of pure product, 3-(3-benzyl-S-chloro-Z-hydroxybenzyl)- 18 3-azabicyclo[3.2.2]nonane, M.P. 109112 C., were obtained.

Analysis.Calcd for C H Cl NO: C, 53.81; H, 5.40; N, 4.18. Found: C, 54.00; H, 5.45; N, 4.03.

EXAMPLE XLIII 3-methyl-3-(3-benzyl-5-chloro-2-hydroxybenzyl)-3- azoniabicyclo[3.2.2]nonane iodide Following the procedure of Example 1 H, the compound 3 (3 benzyl 5 chloro-2-hydroxybenzyl)-3-azabicyclo [3.2.2]nonane can be reacted with methyl iodide to yield '3 methyl 3 (3 benzyl-5-chloro-Z-hydroxybenzyl)-3 azoniabicyclo[3.2.2]nonane iodide.

EXAMPLE XLIV A prior art compound: 3-(5-chloro-2-hydroxybenzyl)-3- azabicyclo[3.2.2]nonane hydrochloride This known compound, which will be referred to as M-1503, resulted as the only product isolated and identifiled from an attempt to synthesize 2,6-di-[3-(3-azabicyclo [3.2.2]nonyl)methyl] 4-chlorophenol. M-1503 is a known compound described by C. De Witt Blanton, Jr. and W. Lewis Nobles in the Journal of Pharmaceutical Sciences, 53, pp. 1130-1132 (1964).

A solution of 73 g. (0.582 mole) of 3-azabicyclo[3.2.2] nonane and 25 g. (b. 194 mole) of 4-chlorophenol in 1000 ml. of absolute methanol was stirred in a 2000 ml. threenecked flask equipped with a stirrer, thermometer, condenser and dropping funnel. To this solution was added, dropwise with stirring at 10 C., 40.6 g. (0.485 mole) of 36% aqueous formaldehyde solution.

After the addition was completed, the mixture was stirred at room temperature for one hour and stirred under reflux for two hours. After stirring under reflux for two hours, the reaction mixture was allowed to stand at room temperature for four days. The solvent and water were distilled from the reaction mixture under reduced pressure. The residue, a clear, light brown oil was shaken with 300 ml. of 3 N hydrochloric acid and 300 ml. of anhydrous ethyl ether was added. A white solid formed and was filtered under suction. The solid which was obtained was dried at 60 C. The dried solid weighed 52.3 g., M.P. 200-220" C. with decomposition.

Repeated recrystallizations of the solid from hot ethanol failed to yield a product which could be identified. However, one of the filtrates upon chilling yielded a white solid weighing 1.7 g., M.P. 245247 C. This product, after three recrystallizations from hot ethanol yielded a white, constant melting solid weighing 0.2 g., M.P. 249-250 C. This material proved to be M-1503 as shown by analysis and melting point which was in the vicinity of that of the compound reported by Blanton and Nobles (M.P. 244-246 C.).

Analysis.-Cald for C H Cl NO: C, 59.61; H, 7.00; N, 4.64. Found: C, 59.73; H, 7.24; N, 4.77.

This preparation was repeated with slight modifications and the product which was isolated was shown to be identical by melting point and mixed melting point with M-1503. It was tested and found to lack activity against bacteria and to have only very slight activity against fungi,- the results obtained being as follows:

To further detail how to use the compounds of the present invention which have antimicrobial activity, the following specific illustrations are presented utilizing the most preferred compounds. Naturally, any compound 1 9 used in any illustration could be used as the antimicrobial agent in any other illustration.

INSTRUMENT DISINFECTANT A surgical instrument disinfectant can be prepared from the following components:

FLOOR DISINFECTANT A fioor and wall disinfectant can be prepared from the following components:

3-dodecyl-3-methyl 3 azoniabicyclo[3.2.2]nonane iodide g 10.0 Dimethylformamide ml 500 Water ml 500 Varying amounts of the nonane compound to give a range of percentages up to 1% can be used depending upon the degree of effectiveness required.

THERAPEUTIC LOTION A therapeutic lotion can be prepared from the following components:

3-(3,5-dichloro-2-hydroxybenzyl) 3 azabicyclo- [3.2.2]nonane hydrogen oxalate g 18.5 Absolute ethyl alcohol ml 750 Distilled water ml 1000 A therapeutic soap can be prepared by compressing the following components into soap cakes:

3-decyl 3 azabicyclo[3.2.2]nonane hydrogen tartrate 1.0 Soap granules (Ivory) 99.0

Other quantities of nonane compound ranging from 0.1 g. to 0.9 g. and soap granules from 99.9 g. to 99.1 g. would be effective formulations depending upon the effectiveness required.

THERAPEUTIC OINTMENT A water washable therapeutic ointment can be prepared from the following components:

3 (2-hydroxy-3,5,6-trich1orobenzyl)-3-azabicyclo- [3.2.2]nonane hydroiodide 1.0 Hydrophilic ointment (U.S.P.), q.s 100.0

Varying amounts of components to give a range of percentages of the nonane compound from 0.1% to 1% can be used.

20 ANTIMICROBIAL PLASTICS Varying amounts of 3(3,S-dichloro-2-hydroxybenzyl)- 3 azabicyclo[3.2.2]nonane hydrogen oxalate may be added to plastics formulations to the extent of 0.1% to 1% concentrations of the nonane compound to impart antimicrobial properties to the plastic materials.

ANTIMICROBIAL ADHESIVES Varying amounts of 3-(2-hydroxy-3,5,6-trichlorobenzyl) 3 azabicyclo[3.2.2]nonane hydroiodide may be added to adhesives formulations to the extent of 0.1% to 1% concentrations of the nonane compound to impart antimicrobial properties to the adhesive.

MEDICATE'D SUTURES Various suture materials may be impregnated with a range of amounts of 3-dodecy1-3-methyl-3-azoniabicyclo- [3.2.2]nonane iodide to give sutures containing from 0.1% to 1% concentrations of the nonane compound which would impart antimicrobial properties to the suture.

ANTIMICROBIAL PA'INTS Amounts of 3-decyl-3-azabicyclo[3.2.2]nonane hydrogen tartrate ranging from 0.1% to 1% concentration after addition to paint formulations may be applied to walls as a component of the paint to impart antimicrobial activity to the painted surface.

Various changes and modifications of the invention can be made as will be apparent to persons skilled in the art, and to the extent that such variations incorporate the spirit of this invention, they are intended to be included within the scope of the appended claims.

We claim:

1. Quaternary ammonium salts of 3-0 alkyl-3-azabicyclo[3.2.2]nonane.

2. Acid addition salts of 3-0 alkyl-3-azabicyclo- [3.2.2]nonane.

3. The compounds of claim 2 which are acid addition salts of 3-decyl-3-azabicyclo[3.2.2]nonane.

4. The compound of claim 2 which is 3 dodecyl-3- methyl-3-azoniabicyclo[3.2.2]nonane iodide.

5. The compound of claim 2 which is 3-methyl-3-tetradecyl-3-azoniabicyclo[3.2.2]nonane iodide.

6. The compounds of claim 1 which are the hydrogen oxalate or hydrogen tartrate salts of 3-decyl-3-azabicyclo[3.2.2]nona.ne.

References Cited UNITED STATES PATENTS 3,280,105 10/ 1966 Brown et al. 260-239 BA 3,385,846 5/1968 Herr et al. 260239 'BA OTHER REFERENCES Brown et al.: I&EC Product 'Research and Development, vol. 4, pp. 40-41 (1965).

Gassman et al.: J. Org. Chem., vol. 30, pp. 2859-2861 1965).

ALTON D. ROLLINS, Primary Examiner U .8. Cl. X.R.

mores-sures PATENT UFFICE v ETFIATE F QCTIQN Patent No. Q, 816 L107 Dated June ll, 197

e Hfbward c. 2611 80 Paul M. Borick It is certifled that error appears in the above iden t-ified patent and that said Letters latent are, hereby correczted as shown below:

v In Column llne %0, 'ocrresponc! should read "correspond In fco1umn 1, line 66, H, 11.6; N, LL93" should read In'COIumn 5, line 26, "while" should read "white" In Column 5, line 44, after recr51stallzlzalziolds"' should read "after three recrystallizations" In Column 5, line I 50, "E-deoyl should read "3+Decyl" In Column 7, line 32, "3 7" Should d "3 37" In comm-d 7, line 32, "65.23" should read "63.4?"

In *Column 7, line 32, "1051 should read In Column 9, line 29, "2 of (0.2 1 moleflshomd read "QUml. (0.2

In Column 11, line 16, "C011" should read "c011" In Column 15, line 59, O19L1" should read n un I In co1dmn 16, line 19, 1" should read 1" TUNETED STATES PA'i ENT OFFICE ta s 2 CERTEFECATE @F QORRECTIUN Patent No. Dated Inventor) Howard Zell & Paul Borick.

-41 a j It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown belowz v It Column 16, line 20, vsnouid read 1 In Column 17, line l r, "dic1'1loro2-hydroxybenzyl) 3 -azabicyclo ,2 .2) nonane" should read ".dichloro (3,2 wmanfi 7 Iri Column 19, lines 8, 18, "5510.6" should read ="lO.Og"

Lln Column 19, lines l0, 19, "ml 500" should read 5- ."500 ml" m. It Colunm 19, lilie 11,- 20, "ml 500 should read 4.- "500 m1" In Column 19, line 31, "g 18.5" should read "18. 3 g" Q'BlI-JnQ-n 9 liin 3 "ml 750" should read "750 ml" In Column 9 33, "M1 1000" should read #1000 m1" si med. and. sealed this llth 'da of February 1975,

" lam.)

' fittest:

RUTH C W501? v C a MARSHALL DANN -f ttresting Officer Commissioner of. Patents and Trademarks F OR PO-IOSO (10-69) 

